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Dithranol Targets Keratinocytes, Their Crosstalk with Neutrophils And

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Dithranol Targets Keratinocytes, Their Crosstalk with Neutrophils And RESEARCH ARTICLE Dithranol targets keratinocytes, their crosstalk with neutrophils and inhibits the IL-36 inflammatory loop in psoriasis Theresa Benezeder1†, Clemens Painsi2†, VijayKumar Patra1, Saptaswa Dey1, Martin Holcmann3, Bernhard Lange-Asschenfeldt2, Maria Sibilia3, Peter Wolf1* 1Department of Dermatology, Medical University of Graz, Graz, Austria; 2State Hospital Klagenfurt, Klagenfurt am Wo¨ rthersee, Austria; 3Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Abstract Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs. *For correspondence: [email protected] †These authors contributed equally to this work Introduction With the development and market introduction of biologics, much progress has been made in recent Competing interests: The years in the systemic treatment of psoriasis. Currently, targeted therapy with antibodies against IL- authors declare that no 17 or IL-23 exhibits high efficacy and allows complete or almost complete clinical clearance of psori- competing interests exist. asis lesions in a high percentage of cases (Blauvelt et al., 2017; Langley et al., 2014; Papp et al., Funding: See page 24 2017; Reich et al., 2018). However, patients with limited body area involvement (i.e. mild forms of Received: 17 March 2020 psoriasis) who represent the majority of psoriasis patients with up to 90% (Stern et al., 2004) have Accepted: 18 May 2020 been neglected. Not much innovation has occurred in the past few years on topical treatment of Published: 02 June 2020 psoriasis that is mainly prescribed to these patients. Steroids, vitamin D3 and vitamin A analogues are most commonly used as topical agents in such patients, but besides changes in their pharmaceu- Reviewing editor: Ulrich Mrowietz, Christian-Albrechts- tical formulation, they have not been developed further in recent years (de Korte et al., 2008; Universita¨ t zu Kiel, Kiel, Germany Krueger et al., 2001; Langley et al., 2011; Schaarschmidt et al., 2015). Short courses of dithranol (1,8-dihydroxy-9-anthracenone or anthralin) have been successfully used as intermittent topical treat- Copyright Benezeder et al. ment of psoriasis since 1916 (Nast et al., 2012; Sehgal et al., 2014; Vleuten et al., 1996). Despite This article is distributed under its numerous disadvantages like brown staining and irritation of perilesional skin, dithranol has the terms of the Creative Commons Attribution License, remained one of the most effective topical treatment modalities in psoriasis. Analogous to the most which permits unrestricted use recent generation of biologics (including anti-IL-17 and anti-IL-23 antibodies), dithranol delivers and redistribution provided that PASI75 rates in 66–82.5% of patients with fast action and clearance of skin lesion within very few the original author and source are weeks (Keme´ny et al., 1990; Painsi et al., 2015b; Sehgal et al., 2014; van de Kerkhof, 2015). credited. Although dithranol has been used for many years, its exact mechanism of action has remained Benezeder et al. eLife 2020;9:e56991. DOI: https://doi.org/10.7554/eLife.56991 1 of 31 Research article Immunology and Inflammation largely unknown (Holstein et al., 2017; Keme´ny et al., 1990; Kucharekova et al., 2006; Sehgal et al., 2014). With the aim of unraveling dithranol’s therapeutic mechanisms and to possibly uncover new tar- gets for topical treatment of psoriasis, we conducted a clinical trial and employed several mouse models including the c-Jun/JunB knockout model (Zenz et al., 2005) and the imiquimod psoriasis model (van der Fits et al., 2009) in order to address this issue and elucidate dithranol’s effects. In this study, we demonstrate that dithranol exerts its anti-psoriatic effects by directly targeting kerati- nocytes and their crosstalk with neutrophils, as well as disrupting the IL-36 inflammatory loop. Con- sistent with this finding, we observed that dithranol’s therapeutic activity was completely independent of its pro-inflammatory effect mainly on perilesional skin, thus overthrowing the long- believed paradigm that dithranol-induced irritation is crucial for its anti-psoriatic action and unravel- ing irritation merely as a bystander effect of treatment. Results Topical dithranol leads to fast reduction in PASI score linked to decrease in epidermal hyperproliferation and delayed reduction of inflammatory infiltrate in psoriatic skin As depicted in Figure 1C (and Figure 1—figure supplement 1), dithranol did lead to a fast reduc- tion of psoriatic skin lesions in most of the 15 patients of the study, as determined by psoriasis area and severity index (PASI) and local psoriasis severity index (PSI) of marker lesions. As shown in Table 1, the mean decrease in PASI score was 58% after 2–3 weeks, confirming its high clinical effi- cacy (Painsi et al., 2015a; Painsi et al., 2015b; Swinkels et al., 2004). Remarkably, dithranol treat- ment did lead to a visible inflammatory response only at perilesional skin sites, but not within psoriatic plaques and there was no correlation between dithranol-induced erythema and its anti-pso- riatic effect (Figure 1—figure supplement 2). The clinical response was confirmed by the results of histological analysis of skin biopsies taken throughout the dithranol treatment course (Figure 1A and B). Dithranol application led to a significant reduction in epidermal hyperplasia (as measured by thickness of epidermis). Intriguingly, there was no significant change in dermal infiltrate score during treatment. At the follow-up visit, hyperplasia of the epidermis was reduced further and cellular infil- trate in the dermis was significantly diminished (Figure 2). Clinical response to dithranol in psoriasis patients is linked to I) fast upregulation of keratinization genes and downregulation of neutrophil chemotactic genes and neutrophilic infiltration followed by II) delayed downregulation of inflammatory response-related genes and proteins Dithranol slowly diminished CD3, CD4, FoxP3 and CD8 cell counts in the dermis as evidenced by unaffected cell numbers early on during the treatment course and significant reduction only at the follow-up visit (4–6 weeks after end of treatment) (Figure 2). The response of T cells in the epidermis occurred a little earlier, with significant reduction present already at the end of treatment (week 2–3) (Figure 2). In agreement with other studies (Holstein et al., 2017; Swinkels et al., 2002a; Vleuten et al., 1996; Yamamoto and Nishioka, 2003), we found a fast decrease in epidermal hyperproliferation (epidermal thickness, Ki-67 and CK16 staining) at end of treatment (week 2–3). Neutrophil numbers (as assessed by myeloperoxidase staining) in epidermis and dermis were also significantly reduced at that time point. An increase in the number of Langerhans cells in the epider- mis (as indicated by CD1a staining) was detected at the follow-up visit. Microarray analysis comparing lesional skin at day 6 of treatment with lesional skin samples at baseline revealed that dithranol led to differential expression of 62 genes including 17 genes with reduced and 45 genes with increased expression. Among these differentially expressed genes (DEGs), there was a significant upregulation of genes involved in keratinization and keratinocyte dif- ferentiation (e.g. KRT2, LCE1C, KRT73, LCE1A) and establishment of skin barrier (e.g. FLG2, HRNR, FLG). Furthermore, dithranol downregulated genes of antimicrobial peptides (AMPs) such as ß- defensin-2 (DEFB4A, DEFB4B) and chemoattractants for neutrophils (e.g. CXCL5, CXCL8, PPBP1, TREM1)(Table 2). Benezeder et al. eLife 2020;9:e56991. DOI: https://doi.org/10.7554/eLife.56991 2 of 31 Research article Immunology and Inflammation ! " Biopsy sampling Non-lesional skin 1b 2 1a 4 3 Psoriasis patients n = 15 Marker lesion Dithranol # !"#$% !"#$/ 012$'3 456"47614 8'))'9:;< &'(") *+,-$.. &'(") *+,-$/ &'(") *+,-$= &'(") *+,-$. Figure 1. Dithranol leads to a fast reduction of psoriatic skin lesions as determined by local psoriasis severity index (PSI) of marker lesions. (A,B) 15 psoriasis patients were treated with dithranol. Skin biopsies were taken from marker lesions at multiple timepoints: 1a = lesional skin at baseline, 2 = lesional skin at day 6, 3 = lesional skin at end of treatment, week 2–3, 4 = lesional skin at follow-up, 4–6 weeks after end of treatment. In addition, non-lesional skin at baseline (1b) was sampled. (C) Representative images of lesional psoriatic skin and
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